Alzheimer's disease (AD) is one of the largest unmet medical need today. Epidemiologic data indicate that this need will mushroom in the coming decade unless new therapeutic options are identified. Pathological and human genetic studies have made substantial progress in supporting an Amyloid Hypothesis of AD and efforts to remove amyloid-A (A) immunologically, to block A production by secretases and enhance A degradation are advancing. However, a cell biological understanding of how A is toxic for neurons has lagged. Recent studies have focused attention on soluble oligomers of A as culprits in the disease process in both correlative and functional studies. The neuronal targets by which oligomeric A mediates neuronal dysfunction are unknown but their identification would provide a novel pathway in drug development. In Preliminary Studies, we have identified the cellular Prion Protein (PrPC) as an A-oligomer receptor by expression cloning. Synaptic responsiveness in brain slices from young adult PrP null mice is normal, but the A-oligomer blockade of long-term potentiation (LTP) is absent. Thus, PrPC is a mediator of A- oligomer induced synaptic dysfunction in vitro. Here, we will determine if the same molecular interaction plays a role in A-induced memory dysfunction and neurodegeneration. We will determine the requirements for specificity in this interaction and explore downstream signaling pathways. Together, this work holds the promise of validating a novel therapeutic target for AD, one that is based not on A levels but on preventing the deleterious actions of A-oligomers on neurons through a specific binding site.